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cGAS regulates the DNA damage response to maintain proliferative signaling in gastric cancer cells
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作者 BIN LIU HAIPENG LIU +12 位作者 FEIFEI REN HANGFAN LIU IHTISHAM BUKHARI YUMING FU WANQINGWU MINGHAI ZHAO SHAOGONG ZHU HUI MO FAZHAN LI michael b.zheng YOUCAI TANG PENGYUAN ZHENG YANG MI 《Oncology Research》 SCIE 2021年第2期87-103,共17页
The activation of some oncogenes promote cancer cell proliferation and growth,facilitate cancer progression and metastasis by induce DNA replication stress,even genome instability.Activation of the cyclic GMP-AMP synt... The activation of some oncogenes promote cancer cell proliferation and growth,facilitate cancer progression and metastasis by induce DNA replication stress,even genome instability.Activation of the cyclic GMP-AMP synthase(cGAS)mediates classical DNA sensing,is involved in genome instability,and is linked to various tumor development or therapy.However,the function of cGAS in gastric cancer remains elusive.In this study,the TCGA database and retrospective immunohistochemical analyses revealed substantially high cGAS expression in gastric cancer tissues and cell lines.By employing cGAS high-expression gastric cancer cell lines,including AGS and MKN45,ectopic silencing of cGAS caused a significant reduction in the proliferation of the cells,tumor growth,and mass in xenograft mice.Mechanistically,database analysis predicted a possible involvement of cGAS in the DNA damage response(DDR),further data through cells revealed protein interactions of the cGAS and MRE11-RAD50-NBN(MRN)complex,which activated cell cycle checkpoints,even increased genome instability in gastric cancer cells,thereby contributing to gastric cancer progression and sensitivity to treatment with DNA damaging agents.Furthermore,the upregulation of cGAS significantly exacerbated the prognosis of gastric cancer patients while improving radiotherapeutic outcomes.Therefore,we concluded that cGAS is involved in gastric cancer progression by fueling genome instability,implying that intervening in the cGAS pathway could be a practicable therapeutic approach for gastric cancer. 展开更多
关键词 Gastric cancer Cell proliferation cGAS DNA damage response MRN complex
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